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Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.

ABSTRACT: In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFR? is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFR? has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development.To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination.By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFR? resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed.Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.

SUBMITTER: Smith CL

PROVIDER: S-EPMC3134964 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.

Smith Christopher L CL Baek Seung Tae ST Sung Caroline Y CY Tallquist Michelle D MD

Circulation research 20110421 12

<h4>Rationale</h4>In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development.<h4>Objective</h4>To understand the contribution of PDGF receptors in epicard ...[more]

PMID: 21512159

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Project description:Epithelial-mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-β (TGFβ) is a potent inducer of this cellular transition, which is composed of transitions from an epithelial state to intermediate or partial EMT state(s) to a mesenchymal state. Using computational models to predict cell state transitions in a specific experiment is inherently difficult for reasons including model parameter uncertainty and error associated with experimental observations. In this study, we demonstrate that a data-assimilation approach using an ensemble Kalman filter, which combines limited noisy observations with predictions from a computational model of TGFβ-induced EMT, can reconstruct the cell state and predict the timing of state transitions. We used our approach in proof-of-concept "synthetic" in silico experiments, in which experimental observations were produced from a known computational model with the addition of noise. We mimic parameter uncertainty in in vitro experiments by incorporating model error that shifts the TGFβ doses associated with the state transitions and reproduces experimentally observed variability in cell state by either shifting a single parameter or generating "populations" of model parameters. We performed synthetic experiments for a wide range of TGFβ doses, investigating different cell steady-state conditions, and conducted parameter studies varying properties of the data-assimilation approach including the time interval between observations and incorporating multiplicative inflation, a technique to compensate for underestimation of the model uncertainty and mitigate the influence of model error. We find that cell state can be successfully reconstructed and the future cell state predicted in synthetic experiments, even in the setting of model error, when experimental observations are performed at a sufficiently short time interval and incorporate multiplicative inflation. Our study demonstrates the feasibility and utility of a data-assimilation approach to forecasting the fate of cells undergoing EMT.

Dataset Information

Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.

Publications

Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.

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